University of South Florida

Vanderbilt University

University of California

The University of Texas System

Edwin John Weeber

Melinda Marie Peters

Lisa Zhao

Dominic Paul D'Agostino

Hana Marie Soueidan

Qingyou Li

Stephanie Lynn Ciarlone

Stephen E Saddow

Christopher Leroy Frewin

Scott Victor Dindot

David J Segal

Kevin Ron Nash

Jennifer Leigh Daily

Henriette O'Geen

Benjamin Pyles

The present invention concerns non-human animals with cells having a genome that is lacking the entire E3 ubiquitin ligase (Ube3a) gene (including all isoforms and alternative promoters). These animals are useful for modeling Angelman Syndrome. The invention also includes methods for assessing the effect of an agent, such as potential therapeutics, on an animal model by exposing the animal or cells, tissues, or organs isolated therefrom, to an agent of interest.

Animal model of Angelman Syndrome

Disclosed herein are compounds for activating the Reelin signaling system for the treatment of neurological disorders Further provided are compounds and methods for activating a lipoprotein receptor, such as ApoER2 or VLDLR.

Drug-induced activation of the Reelin signaling system

Angelman Syndrome (AS) is a genetic disorder occurring in approximately one in every 15,000 births. It is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes for E6-AP, an ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. We have generated a Ube3a protein with additional sequences that should allow the secretion from cells and uptake by neighboring neuronal cells. This would confer a functional E6-AP protein into the neurons and rescue disease pathology.

Modified UBE3A gene for a gene therapy approach for angelman syndrome

Disclosed herein are compounds for activating the Reelin signaling system for the treatment of neurological disorders. Further provided are compounds and methods for activating a lipoprotein receptor, such as ApoER2 or VLDLR.

Disclosed are methods of influencing, and enhancing, cognitive function and memory by increasing, and/or preventing interference with, Reelin levels as well as Reelin signaling. Cognitive function is improved, in a subject in need thereof, by administering a therapeutically effective amount of Reelin, a Reelin-specific modulator or an agonist of a lipoprotein receptor to the subject. The lipoprotein receptor can be selected from candidates such as ApoER2 and VLDLR. As disclosed herein, agonists of the lipoprotein receptor for use with the inventive method include APC, Sep and Fc-RAP. In addition to administering exogenous Reelin, a Reelin-specific modulator, such as a recombinant Reelin fragment, can be used to increase Reelin levels and/or signaling.

Reelin rescues cognitive function

Disclosed are methods of influencing, and enhancing, cognitive function by increasing, and/or preventing interference with, Reelin levels as well as Reelin signaling. Cognitive function is improved, in a subject in need thereof, by administering a therapeutically effective amount of Reelin, a Reelin-specific modulator or an agonist of a lipoprotein receptor to the subject. The lipoprotein receptor can be selected from candidates such as ApoER2 and VLDLR. As disclosed herein, agonists of the lipoprotein receptor for use with the inventive method include APC, Sep and Fc-RAP. In addition to administering exogenous Reelin, a Reelin-specific modulator, such as a recombinant Reelin fragment, can be used to increase Reelin levels and/or signaling.

The invention concerns a method of treating Angelman Syndrome (AS) in a subject, comprising inducing ketosis in the subject by administering a therapeutically effective amount of a ketone ester, such as an R,S-1,3-butanediol acetoacetate ester, wherein administration of the ketone ester elevates the blood ketone level in the subject. Other aspects of the invention include a method of increasing cognitive function and/or motor function in a subject with AS; and a method of decreasing seizures and increasing the latency to seize in a subject with AS.

Ketone supplements for treatment of angelman syndrome

Ketone esters for treatment of angelman syndrome

Reelin rescues congnitive function

An implantable neuronal prosthetic and method of manufacture thereof includes at least one elongated electrode shank adapted for arrangement in the brain having at least one electrode contact disposed on its surface and arranged to electrically couple with said brain. The at least one elongated electrode shank is formed form a single crystal cubic silicon carbide. An insulation layer of amorphous, polycrystalline, or single crystal silicon carbide is disposed over the elongated electrode shank; the insulation layer of amorphous, polycrystalline, or single crystal silicon carbide is removed from the at least one electrode contact. Signal control electronics are attached to the at least one elongated electrode shank and are in electrical communication with the at least one electrode contact. In an embodiment, a plurality of the at least one elongated electrode shanks are arranged into a matrix.

Growing community of inventors

Apollo Beach, FL, United States of America

Edwin John Weeber